6 Cortical thickness reaches a developmental nadir while myelin continues to increase
7 Normal myelination/general MRI patterns Need to know what is normal to know what is not normal.Neonate: T1 hypo T2 hyperFully myelinated: T1 hyper T2 hypoT1 signal increases with increasing cholesterol and galactocerebrosideT2 signal decreases with decreasing amount of brain waterdisplaced by myelinIncreased length hydrocarbons and double bondsT2 changes lag behind T1 changes
8 General Patterns of myelination Rostral to caudalPosterior to anteriorCentral to peripheral
19 Components of myelin: Sheath: protein-lipid-protein-lipid-protein Glycolipids: glalctocerebroside, sulfatide, cholesterolOuter layer of membraneLong chain fatty acids (middle)Phospholipids:Hydrophobic, on inner membraneOthers: MAG, MOG, PLP, MBP, CNPase
20 LeukodystrophiesGenetic, with degeneration of myelin sheaths in CNS (+/-) PNSRelated to synthesis and maintenance of myelin membranes.Vast majority autosomal recessiveLeukoencephalopathies: defects causing secondary myelin damageDiagnosis requires a clinical strategy
23 Clinical presentation Insiduous, in a previously healthy child.Slowly progressing, may have periods of stagnationVague/progressive motor and mental symptoms.Widely variable phenotypes associated with single genetic diseasePresents from infancy to adulthood.
25 Exam Physical abnormalities uncommon Neurologic (progressive): Big head: Alexander, Canavan, megalencephalic leukodystrophy with cysts and vanishing white matterDysmorphic features similar to mucopolysacharidoses: fucosidosis, MLDNeurologic (progressive):Motor (spasticity)Changes in cognition and languageSeizures are rarePeripheral nerve (MLD, globoid cell, hypomyelination)
26 Diagnosis: MRI most important test Stepwise approach:Hypomyelination?Differentiate delayed vs. permanent with serial MRI studiesConfluent, bilateral, symmetric wm lesions c/w genetic disease vs. multifocal or asymmetric with acquired diseaseIf confluent lesions are present, what is the localization? (frontal, parieto-occiptial, periventricular, subcortical, diffuse, posterior fossa)
32 Additional imaging MRS CT: better than MRI for calcifications NAA elevated in CanavanDecreased NAA suggests neuronal involvement in primary WM diseaseLactate in “leukencephalopathy with brainstem and spinal cord involvement and elevated lactate”Other mitochondrial disordersCT: better than MRI for calcifications
33 Globoid cell leukodystrophy Swelling of optic nervesContrast enhancement of spinal roots+/- peripheral nerve thickening
34 Electrophysiology NCS Evoked potentials Symmetric involvement of long spinal tracks and peripheral nervesMay help differentiate leukodystrophiesNormal in X-ALD, usually abnormal with metachromatic or globoid cellCorrelates with severity of clinical diseaseEvoked potentialsBAER abnormal first, then SSEP lower limbs, then MEPs of lower limbs
35 Tests to consider early on in evaluation. Low yield of done prior to exam and evaluation of imaging.
36 Other organ systems Optho Endocrine GI Cataracts Cerebrotendinous xanthomatosisSome forms of hypomyelinationCherry red spot: differentiate infantile/macrocephalic leukodystrophies from GM2 gangliosidosisSuch as Tay-Sachs and SandhoffEndocrineAddison’s disease +/- neuro invovlement in X-ALDOvarian failureGIFeeding and swallow issues are common.Gallbladder papilloma in MLD
37 Treatment Prognosis is dismal Supportive care Swallow eval/g-tube Abx when indicatedAntispasmodics and pain control.ACTH monitoring/stress dose steroids
38 Treatment Continued Lorenzo’s oil in X-ALD Bone Marrow transplantation Erucic and oleic acidLowers VLC FAsBenefits asymptomatic boysBone Marrow transplantationCan halt progression in X-ALD, but…2/3 boys develop cerebral disease, and…Successful only in early stages of disease.Gene therapyExperimentalTherapeutic window is narrowAsymptomatic____ Too far gone
39 Leukodystrophies, in Summary: Incurable with progressive motor and mental disabilityLeukodystrophy if due to myelin sheath, leukoencephalopathy if outside. (similar)White matter and gray matter disease may overlap.Definitive diagnosis is challenging, though timely diagnosis is required.
40 Summary continued, Diagnosis through: Physical examinationMRI imagingWith help from targeted laboratory testingImportant for family counseling and optimization of carePalliativeexperimental
41 ReferencesWelker and Patton. Assessment of normal myelination with magnetic resonance imaging. Semin Neurol ;32:15-28.Kohlshutter and Eichler. Childhood leukodystrophies: a clinical perspective. Expert Rev. Neurother. 2011;11: